Download Dogs: Active Role Model for Cancer Studies—A Review

Journal of Cancer Therapy, 2013, 4, 989-995
http://dx.doi.org/10.4236/jct.2013.45113 Published Online July 2013 (http://www.scirp.org/journal/jct)
989
Dogs: Active Role Model for Cancer Studies—A Review
Sana Munaf Hawai1,2, M. Al-Zayer1,2, Mohammed M. Ali1,2, Yuanjie Niu3,4,5, A. Alawad6, M. Aljofan2,
A. Aljarbou7,8, S. Altuwaijri1,2,3,4,5,6,7
1
Saad Research and Development Center, Clinical Research Laboratory, SAAD Specialist Hospital, Al Khobar, Saudi Arabia;
College of Pharmacy, Qassim University, Qassim, Saudi Arabia; 3Tianjin Institute of Urological Surgery, Tianjin Medical University, Tianjin, China; 4Department of Surgery, University of Michigan, Medical Center, Ann Arbor, USA; 5George Whipple Lab for
Cancer Research, Departments of Pathology, Urology and Oncology, University of Rochester Medical Center, Rochester, USA;
6
King Abdulaziz City of Science and Technology, Riyadh, Saudi Arabia; 7College of Applied Medical Science, Qassim University,
Qassim, Saudi Arabia; 8Al Ghad International Medical Science Colleges, Riyadh, Saudi Arabia.
Email: [email protected]
2
Received April 20th, 2013; revised May 22nd, 2013; accepted May 30th, 2013
Copyright © 2013 Sana Munaf Hawai et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ABSTRACT
Many studies have been done and many results have been established for studying cancers in human and the ways of
treating it. However, one thing that remains relevant is the study model that is used to diagnose, cure or conclude treatment methods for human cancers. The scientists have tried some ways to link the data and tried to analyze the malicious
disease in various animal models in order to solve the problem for humans. Out of all the models, scientists have preferred dogs as the most suitable model and conducted studies on them. Our article will review the reason for preferences
given to dog as a study model and what the previous studies have tried to conclude by considering the dreaded disease
in dogs. Our article has focused on most of the recent observations and tried to elucidate the reasons/preferences for
studying cancer disease in dogs (scientific name; Canis Lupus familiaris). We will also talk about the idea of comparative oncology programs that many centers adapt in order to study the disease called cancer.
Keywords: Cancer; Models; Dogs; Comparative; Oncology
1. Introduction
The most common type of tumor in unspayed female
dogs is the mammary tumor especially between the ages
of five to 10 years. Some male dogs do develop this type
of breast cancer, but due to the hostility of this type of
breast cancer, the prognosis is not good. Mammary tumors in dogs range in size and often grow quickly with
an irregular shape. These malignant tumors can also root
bleeding and ulceration [1]. There were an estimated
12.7 million cancer cases around the world reported in
2008, out of which 6.6 million cases were in men and 6.0
million in women. This number is expected to increase to
21 million by 2030 [2]. According to the statistics in
2011, 230,480 new cases of invasive breast cancer are
estimated to be diagnosed in women in the US, along
with 57,650 new cases of non-invasive (in situ) breast
cancer [3].
Breast cancer being the most common cancer in
women, is responsible for almost 20% of all cancer
deaths in women. Increase in awareness and routine
mammograms has helped women to get diagnosed in
Copyright © 2013 SciRes.
earlier stages of breast cancer thereby increasing the
chances of curing it. The statistics state that for every 100
women, one man is also diagnosed with this disease. The
disease is more common in women above 40. It is also
more frequent in women of a higher social-economic
class [4].
2. The Reason behind Dog
The inspiration behind comparative oncology is simple.
If a model is very similar to human beings then why
can’t we investigate it to introduce quality improvement
for human healthcare? Dogs get many cancers that strike
humans, including lymphoma, breast cancer and bone
cancer. Contrasting to genetically altered laboratory animals that we used to test potential new cancer treatments,
dogs develop this disease naturally. We can measure the
same things in dog that we do in humans, like heart
changes, organ function and blood pressure. Hence, these
data can be applied directly to human diseases. With
dogs, we can ask many questions that one cannot ask in
mouse preclinical models of cancer and cannot answer in
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Dogs: Active Role Model for Cancer Studies—A Review
human clinical trials.
Treating naturally occurring diseases of dogs does not
create an ethical issue as seen with experimentally induced disease in models and hence it provides a more
robust model. The physiology of dog allows responding
to drug metabolism in way comparable to humans,
therefore the dog is used routinely for pharmaceutical
toxicological studies [5]. Cancer is the most recurrent
canine disease. Dogs develop spontaneous tumors that
display behavior and histo-pathological characteristics to
human tumors [6-8]. For example, in dogs, studying
about the role of inhibition of telomere size shortening
plays in cell immortalization and proliferation is relevant,
because dog chromosomal telomeres closely resemble
human telomeres than murine telomeres [9]. Among the
practical benefits of clinical investigation of cancer in
dogs is the fact that due to their shorter life span, clinical
intervention is easily studied over a condensed period of
time. The dog cancer cases have the survival rate over
one year, rather than five, as in human oncology [8], thus
the possibility to attain comparatively rapid results when
performing clinical trials and monitoring disease progression in dogs.
2.1. Why Not Mouse as Models?
Murine models have been used in many studies, but in
vivo murine model such as xenografts and transgenics
fail to reiterating essential features and characteristics
(such as heterogeneity, tumor microenvironment and
dependence on steroid hormones) of human breast cancer
[10,11]. In addition to the inherent evolutionary remoteness between mice and humans, further differences can
originate due to induced genetic modifications (transgenic mice) or from altered presence of adjacent normal
tissue, stromal cells, vasculature and immune system
components (xenografts) [12-16]. Jointly these factors
explain the limited values of murine model for studying
cancer pathogenesis, progression and therapy and embody a major obstacle in identifying of reliable predictive
molecular biomarkers and effective therapeutic agents
development [10,17].
2.2. Studying Cancer with Dog Models
Of all the disorders for which dogs are likely to enlighten
human health, canine cancer is likely to have the greatest
effect [18]. Cancer is the most frequent cause of diseaseassociated death in canines, and naturally occurring cancers have been well described in several breeds [19-21].
Although, substantial effort has been spent in studying
common cancers, the dog has always serves as a model
for rare tumors studies, including aggressive histiocytic
sarcoma and lethal dendritic-cell neoplasms [22].
A mammary tumor is the common kind of tumor in
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unspayed female dogs. Similarly, breast cancer is the
most widespread cancer in women, striking 1/8th women
during their lifetime. Not all dogs or even women succumb to the disease. Many individuals have benign slow
growing tumors, which are curable. In other cancerous
cells grow profusely and metastasize. But like in studies
done in rats or mice, caner researchers don’t induce caner
in dogs. Instead, the cancer is so commonly found in
these models that the researchers compassionately treat
them naturally. Another reason why canines render help
in studying mammary tumor is the fact that each female
has eight to ten mammary glands thereby making it probable to study several tumors—each cropping up separately from the other and therefore genetically unique-in
one individual. However, studying separate breast tumors
in humans is usually not possible because it is rare for a
woman to develop more than one spontaneous tumor in
the breast [23].
2.3. Need for More Predictive Preclinical Models
Due to cancer complexity and limited knowledge available in this arena, many animal models fall short of predictive. The information we try to decipher from these
models comes to a limited scope every now and then.
Also, it can be said that even humans are not prognostic
models when it come to cancer studies. When considering the evaluation of novel therapy in a species distinct
from humans, it should be essential to ensure that questions asked in preclinical models can be answered and
certify the interpretation of answers within the totality of
information available [24]. Murine cancer models have
proved to be useful for analyzing the complicated pathways involved in cancer initiation, promotion and progression. However, they have proved incapable in defining features occurring in humans like long latency periods, genetic instability, and heterogeneity of tumor cells.
Most important of all; the complex biology of cancer,
recurrence and metastasis, which is an outcome in human
patients, fails to be explained in the conventional mouse
models and in cancer drug development. Thus, the needs
for additional models that represent the human disease in
an enhanced way are needed [24].
According to leading cancer researchers, dogs have
proved to be good research subjects as they develop the
disease spontaneously, and many of the modern breeds
have developed over the past few hundred years using
restricted gene pools. Due to this selective breeding, the
breed genetics have been preserved and has made some
breeds more susceptible to certain cancers. These aspects
along with high grade of similarity between dog and human genomes have helped the researchers to compare
their genomes and study the evolutionary genetic
changes associated with cancer. These factors, coupled
with high degree of similarity between the genomes of
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Dogs: Active Role Model for Cancer Studies—A Review
dogs and humans, which provide the researchers with an
opportunity to compare the genomes and study the evolutionary genetic changes associated with cancer [25].
Another basis for using them as study models deals
with how human drug trials are conducted. The benefit
would be to study and test the treatment strategies in canines with aggressive tumors and monitor how they respond to the treatment. In this way, the comparative oncologists can test new treatment ideas against early-stage
of cancers and delivering the drugs just as they would
ultimately be in cancer patients [25]. This means more
effective treatments can be developed more quickly, with
less adverse health risks, for human trials and ultimately
viable human treatments. Dogs also have shorter life
spans than humans (most unfortunate) meaning scientists
can more quickly determine whether a prevention strategy or therapy has a good chance of improving human
survival rates [18]. Now moving on from the physiological similarities to genetic level, the chance of studying
health and disease in the dog (Canis lupus familiaris) was
significantly expanded with the release of the first public
draft of the canine genome [26-28]. This prospect was
advanced further with the development of high throughput technologies, such as expression and SNP microarrays that are commercially available for the dog nowadays [26,29,30].
Last many years showed the sequencing of entire dog
genome (99% complete, ~2.5 billion base pairs) and the
confirmation of its close similarity with the human genome [31]. For many gene families and those genes
linked to cancer, the relationship between dog and human
gene sequences is found to be much closer than any other
counterparts [32]. When molecular cytogenetic analysis
of canine tumor cells was carried out from hematological
malignancies, it was revealed that the ancestral chromosomal aberrations were preserved in comparable cancers
of human and dog [33,34]. Altered expression of ERBB2
and TP53 genes in mammary carcinomas is similar to the
two species hence, proving alike roles in carcinogenesis
and prospective use as prognostic indicators [35-37].
Similar mutations in oncogenes resulted in different cancer in humans and dogs, a study suggested [38]. For example, a similar mutation in KIT, a tyrosine kinase growth factor receptor, is recognized in both human gastrointestinal stromal tumors (GIST) and dog mast-cell cancers
[38]. Likewise, the intratumoral (cell-to-cell) heterogeneity in human breast tumors also takes place in cognate
dog tumors [39]. Thus the natural consequences of this
heterogeneity that causes the deadly features of human
cancers like acquired resistance to therapy, recurrence
and metastasis.
For nearly two decades now, we have seen a rise in
canine genome utilization to understand the genetic foundation of disorders that are difficult to unravel in humans
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991
[40-42]. Their large size makes the canine families amenable to conventional linkage mapping. This has been
well exemplified in the canine gene search for hereditary
multifocal renal cystadenocarcinoma and nodular dermatofibrosis (RCND) in German shepherds [43]. Also
the canine genome provided an accessible set of validated expression profiles for human gene expression on
both oligonucleotide and cDNA array platforms which,
benefited researchers with several datasets that were publicly available through web-based interactive analytical
tools [26,44-46]. Using similar approach, the availability
of online database of canine normal tissue gene expression profiles will help in silica analysis of canine diseases.
This will promote more rigorous comparative genomic
analysis for humans, rat and dog tissues [47]. These
comparative oncology studies enable identification of
common gene regulatory regions as well as evolutionary
conserved gene expression networks. Remarkable similarities have been found during the analysis of canine and
human orthologous gene expression in their respective
matched tissues [48]. This tissue expression data demonstration has supported in expanding and redefining canine gene ontologies consequently allowing further robust assessment of biological functions. Common inherited human diseases occur due to complex interactions
between multiple genes and environmental factors. Dogs
share a common environment with man, so the selection
of an authentic model for a multifactorial human disease
becomes an easy choice.
3. Genomic Detailing
The position of the dog within mammalian evolutionary
tree also makes it an important channel for comparative
analysis of the human genome [47]. High prevalence of
specific diseases that affect certain breeds suggests that
there are limited numbers of loci underlying for each
disease. This makes the genetic analysis potentially more
traceable in dogs than humans [49]. Within the exception
of human, dog is the most intensely studied animal in
medical practice, with detailed family history and pathology data [50]. Using genetic resources developed
over the past 15years [51-56], researchers have already
identified mutations in genes underlying ~25 Mendelian
diseases [57,58]. Dog is equally important for the comparative analysis of mammalian genome biology and
evolution [47]. The important findings, after studying the
dog’s genome, its gene evolution, haplotype structure
and phylogenetic etc showed the average transposon insertion rate of dog genome lower then humans. Also further comparison showed that ~5.3% of the human genome contained functional elements that have been under
purifying selection in both lineages. Similar patterns of
evolution were observed in functionally related gene sets
in human and dog lineages [47]. Unique unambiguous
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Dogs: Active Role Model for Cancer Studies—A Review
aligned sequences created multi-species synteny maps
showed regions of conserved synteny between dog and
human genome. The total number of breakpoints in humans was found to be substantially lower than that in
dogs while more intra-chromosomal breakpoints were
found in human lineages than dogs [47]. Although, the
level of genomic rearrangement has been much higher in
rodent than in human, comparison with dog shows that
there are regions where the opposite is true. Human chromosome 17 is rich in segmental duplications and gene
families, which may contribute to its genomic fragility
[48].
Gene Expression Profiles of Metastatic
Canine Mammary Carcinomas Overlaps
with Human Breast Cancer Profile
Molecular mechanisms behind lymph node and distant
metastasis in Canines still remain incomplete. Several
studies have been done trying to cover this issue but significant metastasis associated and predictable expression
patterns of single genes have still not been identified in
canine mammary tumor (CMT) [35,59-61]. Global gene
expression profiles that compare metastasizing versus
non-metastasizing CMT are unavailable, whereas several
studies on human breast cancer found to be significant
metastasis associated expression profiles. The latter studies have identified several non-overlapping expression
signatures, which are related to the development of lymph node and distant metastases and worse prognosis [6265]. Moreover, comparison of canine and human expression profiles disclosed an overlap of deregulated genes in
human and canine mammary tumors [66].
The greatest challenge faced by clinical scientists is
the incomplete understanding of genetic basis for complex human disease [62]. Regardless of numerous technological advances in genetics, the progress in this field
has been slow due to the intricate gene-gene interactions
and poorly understood environmental effects [67]. Also,
the identification of these interactions and environmental
influences is difficult to scrutinize in humans due to high
level of genetic heterogeneity [68]. Many genome-wide
association studies (GWAS) identified a small fraction of
genetic basis of complex diseases [69]. And yet disease
heritability is critical to understanding disease risk, the
effects of environment and lifestyle on disease development, and response to treatment.
In one of the studies conducted by Klofleisch et al., a
gene expression profile in CMT associated with early
metastatic spread to lymph node was identified that could
discriminate carcinomas with similar histological features but different metastatic potential. This expression
profile contained several enriched functional gene classes
and had significant overlaps with expression profiles of
metastatic human breast cancer [35]. Med gene literature
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mining also confirmed the similarities found between
canine and human mammary tumors in terms of increased proliferation, altered cell differentiation status
and decreased cell adhesion [59].
Approximately 25% of the deregulated genes in metastatic canine carcinomas were cited in association with
human breast cancer. In this subset of cited genes, a significant enrichment of genes associated with cell cycle
regulation, protein kinases, DNA integrity checkpoint
and protein metabolism was observed [61]. It was therefore likely that gene expression profiles may also predict
metastasis in CMT. Klofleisch et al. concluded that metastatic spread of CMT to the lymph nodes was associated with a gene expression profile of increased cell cycle progression, altered cell differentiation and decreased
growth factor signaling. Several key characteristic of
metastasis associated gene expression are therefore similar between human and canine mammary tumors [35].
4. Conclusions
Comparative oncology has proved to be useful for
clinico-pathological and therapeutic study. It has been
proved beneficial to analyze the particular disease pattern
between two or more than two species. The comparative
oncology program has also focused on genetic history
and the pattern of inheritance in different species and
their correlation. This in turn has proved useful to the
research workers to go into the depth of a particular
study of interest.
The goal of scientific research has been to better understand cancer biology in order to understand cancer diagnosis, treatment and prevention in humans and animals.
It is due to the exchange of ideas and observations between researchers studying human and companion animal cancer that these studies have become more common
and successful.
Clinical and translational studies in dogs don’t face the
same constraints as human trials and hence a platform is
prepared by previous researchers to further continue and
enhance these studies for human betterment. We tried to
sum up previous discoveries and conclusions that were
done by renowned researchers. The focus is to analyze
till where have we succeeded in enabling ourselves utilize this model for prognostic cancer strategies in humans.
With comparative oncology studies researchers have
become more confident in development and validation of
new medical devices. Dog models showed that helical
tomotherapy devices could successfully image, position,
and treat spontaneously occurring tumors [70].
The evolutionary history of dogs, their position as a
family member in many households, and the high level
of health care they receive in our world offer tremendous
opportunities. Alongside this combined with recently
developed genetic resources, makes dogs outstanding
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Dogs: Active Role Model for Cancer Studies—A Review
models for the studying known genetic pathways, discovery of genetic and environmental contributions to
disease, and translational studies in cancer risk, prevention, and treatments [70]. Increased gratitude of the inimitable and comparative values of dog as a model for
diverse human diseases should promote and accelerate
more researches leading to new better treatments and
improved health care for both mankind and his best
friend-the dog. Thus in conclusion our summation is that
Dogs are exceptionally suited for use as an animal model
of complex human disease due to their phenotypic diversity and naturally occurring disease resemblance to human conditions.
REFERENCES
[1]
B. Leder, “Breast Cancer in Dogs,” 2009.
http://www.thebark.com/content/breast-cancer-dogs
[2]
J. Ferlay J, H. R. Shin, F. Bray, D. Forman, C. Mathers
and D. M. Parkin, “Globcan 2008 v2.0, Cancer Incidence
and Mortality Worldwide: IARC Cancer Base No. 10,”
2010. http://globocan.iarc.fr, accessed on day/month/year
[3]
Marisa Weiss, et al., “US Breast Cancer Statistics,” 2012.
http://www.breastcancer.org/symptoms/understand_bc/sta
tistics
[4]
M. H Tirgan, “A Short Review on Breast Cancer,” 19962011. http://www.tirgan.com/brstcan.htm
[5]
D. Smith, C. Broadhead, G. Descotes, et al., “Preclinical
Safety Evaluation Using Nonrodent Species: An Industry/Welfare Project to Minimize Dog Use,” The ILAR
Journal, Vol. 43, Supplement S39-S42, 2002, pp. 39-42.
[6]
[7]
[8]
[9]
E. G. McEwen, “Spontaneous Tumors in Dogs and Cats:
Models for the Study OF Cancer Biology and Treatment,”
Cancer and Metastasis Reviews, Vol. 9, No. 2, 1990, pp.
125-136. doi:10.1007/BF00046339
K. A. Hahn, L. Bravo, W. H. Adams and D. L. Frazier,
“Naturally Occurring Tumors in Dogs as Comparative
Models for Cancer Therapy Research,” In Vivo, Vol. 8,
No. 1, 1994, pp. 133-143.
D. M. Vail and E.G. McEwen, “Spontaneously Occurring
Tumors of Companion Animals as Models for Human
Cancer,” Cancer Investigation, Vol. 18, No. 18, 2000, pp.
781-792. doi:10.3109/07357900009012210
L. Nasir, P. Devlin, T. Mckevitt, et al., “Telomere
Lengths and Telomerase Activity in Dog Tissues: A Potential Model System to Study Human Telomere and Telomerase Biology,” Neoplasia, Vol. 3, No. 4, 2001, pp.
351-359. doi:10.1038/sj.neo.7900173
[10] T. Vargo-Gogola and J. Rosen, “Modeling Breast Cancer:
One Size Does Not Fit All,” Nature reviews Cancer, Vol.
7, No. 9, 2007, pp. 659-672. doi:10.1038/nrc2193
[11] S. Nandi, R. C. Guzman and J. Yang, “Hormones and
Mammary Carcinogenesis in Mice, Rats, and Humans: A
Unifying Hypothesis,” Proceedings of the National Academy of Sciences of the United States of America, Vol. 92,
No. 9, 1995, pp. 3650-3657. doi:10.1073/pnas.92.9.3650
[12] F. Balkwill, K. A. Charles and A. Mantovani, “SmolderCopyright © 2013 SciRes.
993
ing and Polarized Inflammation in the Initiation and
Promotion of Malignant Disease,” Cancer Cell, Vol. 7,
No. 3, 2005, pp. 211-217. doi:10.1016/j.ccr.2005.02.013
[13] S. Goswami, E. Sahai, J. B. Wyckoff, M. Cammer, D.
Cox, F. J. Pixley, E. R. Stanley, J. E. Segall and J. S.
Condeelis, “Macrophages Promote the Invasion of Breast
Carcinoma Cells via a Colony Stimulating Factor-1/Epidermal Growth Factor Paracrine Loop,” Cancer Research,
Vol. 65, No. 12, 2005, pp. 5278-5283.
doi:10.1158/0008-5472.CAN-04-1853
[14] K. L. Schwertfeger, J. M. Rosen and D. A. Cohen,
“Mammary Gland Macrophages: Pleiotropic Functions in
Mammary Development,” Journal of Mammary Gland
Biology and Neoplasia, Vol. 11, No. 3-4, 2006, pp. 229238.
[15] J. W. Pollard, “Role of Colony-Stimulating Factor-1 in
Reproduction and Development,” Molecular Reproduction and Development, Vol. 46, No. 1, 1997, pp. 54-60.
doi:10.1002/(SICI)1098-2795(199701)46:1<54::AID-MR
D9>3.0.CO;2-Q
[16] R. C. Hovey, T. B. McFadden and R. M. Akers, “Regulation of Mammary Gland Growth and Morphogenesis by
the Mammary Fat Pad: A Species Comparison,” Journal
of Mammary Gland Biology and Neoplasia, Vol. 4, No. 1,
1999, pp. 53-68. doi:10.1023/A:1018704603426
[17] N. Erin, W. Zhao, J. Bylander, G. Chase and G. Clawson,
“Capsaicin-Induced Inactivation of Sensory Neurons Promotes a More Aggressive Gene Expression Phenotype in
Breast Cancer Cells,” Breast Cancer Research and Treatment, Vol. 99, No. 3, 2006, pp. 351-364.
doi:10.1038/nbt0906-1065b
[18] C. Khanna, K. Lindblad-Toh, D. Vail, C. London, P.
Bergman, et al., “The Dog as a Cancer Model,” Nature
Biotechnology, Vol. 24, No. 9, 2006, pp. 1065-1066.
doi:10.1038/nbt0906-1065b
[19] A. L. Shearin and E. A. Ostrander, “Leading the Way:
Canine Models of Genomics and Disease,” Disease Models & Mechanisms, Vol. 3, No. 1-2, 2010, pp. 27-34.
doi:10.1242/dmm.004358
[20] R. T. Bronson, “Variation in Age at Death of Dogs of
Different Sexes and Breeds,” American Journal of Veterinary Research, Vol. 43, No. 11, 1982, pp. 2057-2059.
[21] L. E. Maquat, “Defects in RNA Splicing and the Consequence of Shortened Translational Reading Frames,” The
American Journal of Human Genetics, Vol. 59, No. 2,
1996, pp 279-286.
[22] C. Zandonella, “Cancer Collaboration Could Someday
Help Dogs and Their Humans,” 2012.
https://www.princeton.edu/main/news/archive/S33/61/61
S27/
[23] I. K. Gordon and C. Khanna, “Modeling Oppurtunities in
Comparative Oncology for Drug Development,” The
ILAR Journal, Vol. 51, No. 3, 2010, pp. 214-220.
doi:10.1093/ilar.51.3.214
[24] J. Modiano, “Genetic Cancer Link between Humans and
Dogs Discovered,” 2008.
http://www.sciencedaily.com/releases/2008/02/08022811
2011.htm
[25] J. David, W. Waters and K. Wildasin, “The Vital ImporJCT
Dogs: Active Role Model for Cancer Studies—A Review
994
tance of Comparative Oncology: Cancer Clues from
Dogs,” 2006. http://landofpuregold.com/cancer/cop.htm
[26] K. Lindblad-Toh, C. M. Wade, T. S. Mikkelsen, E. K.
Karlsson, D. B. Jaffe, et al., “Genome Sequence, Comparative Analysis and Haplotype Structure of the Domestic Dog,” Nature, Vol. 438, No. 7069, 2005, pp. 803-819.
doi:10.1038/nature04338
[27] H. G. Parker and E. A. Ostrander, “Canine Genomics and
Genetics: Running with the Pack,” PLOS Genetics, Vol. 1,
No. 5, 2005, p. e58. doi:10.1371/journal.pgen.0010058
[28] J.A. Holzwarth, R. P. Middleton, M. Roberts, R. Mansourian, F. Raymond, et al., “The Development of a HighDensity Canine Microarray,” Journal of Heredity, Vol. 96,
No. 7, 2005, pp. 817-820.
[29] M. Paoloni and C. Khanna, “Translation of New Cancer
Treatments from Pet Dogs to Humans,” Nature Reviews
Cancer, Vol. 8, No. 2, 2008, pp. 147-156.
doi:10.1038/nrc2273
[30] R. Thomas, A. Scott, C. F. Langford, S. P. Fosmire, C. M.
Jubala, et al., “Construction of a 2-Mb Resolution BAC
Microarray for CGH Analysis of Canine Tumors,” Genome Research, Vol. 15, No. 12, 2005, pp. 1831-1837.
doi:10.1101/gr.3825705
[31] M. M. Hoffman and E. Birney, “Estimating the Neutral
Rate of Nucleotide Substitution Using Introns,” Molecular Biology and Evolution, Vol. 24, No. 2, 2007, pp 522531. doi:10.1101/gr.3825705
[32] M. Breen and J. F. Modiano, “Evolutionarily Conserved
Cytogenetic Changes in Hematological Malignancies of
Dogs and Humans—Man and His Best Friend Share
More Than Companionship,” Chromosome Research, Vol.
16, No. 1, 2008, pp. 145-154.
doi:10.1007/s10577-007-1212-4
[33] R. Thomas, K. C. Smith, E. A. Ostrander, F. Galibert and
M Breen, “Chromosome Aberrations in Canine Multicentric Lymphomas Detected with Comparative Genomic
Hybridization and a Panel of Single Locus Probes,” British Journal of Cancer, Vol. 89, No. 8, 2003, pp. 15301537. doi:10.1038/sj.bjc.6601275
[34] A. Rungsipipat, S. Tateyama, R. Yamaguchi, K. Uchida,
N. Miyoshi and T. Hayashi, “Immunohistochemical Analysis of c-yes and c-erbB-2 Oncogene Products and p53
Tumor Suppressor Protein in Canine Mammary Tumors,”
Journal of Veterinary Medical Science, Vol. 61, No. 1,
1999, pp. 27-32. doi:10.1292/jvms.61.27
[35] A. Setoguchi, T. Sakai, M. Okuda, K. Minehata, M. Yazawa, T. Ishizaka, T. Watari, R. Nishimura, N. Sasaki, A.
Hasegawa and H. Tsujimoto, “Aberrations of the p53
Tumor Suppressor Gene in Various Tumors in Dogs,”
American Journal of Veterinary Research, Vol. 62, No. 3,
2001, pp. 433-439. doi:10.2460/ajvr.2001.62.433
[36] S. Haga, M. Nakayama, K. Tatsumi, M. Maeda, S. Imai,
S. Umesako, H. Yamamoto, J. Hilgers and N. H. Sarkar,
“Overexpression of the p53 Gene Product in Canine
Mammary Tumors,” Oncology Reports, Vol. 8, No. 6,
2001, pp. 1215-1219.
[37] K. Ozaki, T. Yamagami, K. Nomura and I. Narama,
“Mast Cell Tumors of the Gastrointestinal Tract in 39
Dogs,” Veterinary Pathology, Vol. 39, No. 5, 2002, pp.
Copyright © 2013 SciRes.
557-564. doi:10.1354/vp.39-5-557
[38] A. Porrello, P. Cardelli and E. P. Spugnini, “Oncology of
Companion Animals as a Model for Humans—An Overview of Tumor Histotypes,” Journal of Experimental &
Clinical Cancer Research, Vol. 25, No. 1, 2006, pp. 97105.
[39] K. L. Tsai, L. A. Clark and K. E. Murphy, “Understanding Hereditary Diseases Using the Dog and Human as
Companion Model Systems,” Mammalian Genome, Vol.
18, No. 6-7, 2007, pp. 444-451.
doi:10.1007/s00335-007-9037-1
[40] E. K. Karlsson and K. Lindblad-Toh, “Leader of the Pack:
Gene Mapping in Dogs and Other Model Organisms,”
Nature Reviews Genetics, Vol. 9, No. 9, 2008, pp. 713725. doi:10.1038/nrg2382.
[41] E. A. Ostrander and E. Giniger, “Semper Fidelis: What
Man’s Best Friend Can Teach Us about Human Biology
and Disease,” The American Journal of Human Genetics,
Vol. 61, No. 3, 1997, pp. 475-480. doi:10.1086/515522
[42] T. J. Jónasdóttir, C. S. Mellersh, L. Moe, et al., “Genetic
Mapping of a Naturally Occurring Hereditary Renal Cancer Syndrome in Dogs,” Proceedings of the National Academy Sciences of the United States of America, Vol. 97,
No. 8, 2000, pp. 4132-4137. doi:10.1073/pnas.070053397
[43] L. L. Hsiao, F. Dangond, T. Yoshida, R. Hong, R. V. Jensen, et al., “A Compendium of Gene Expression in Normal Human Tissues,” Physiol Genomics, Vol. 7, No. 2,
2001, pp. 97-104.
[44] A. Saito-Hisaminato, T. Katagiri, S. Kakiuchi, T. Nakamura, T. Tsunoda, et al., “Genome-Wide Profiling of
Gene Expression in 29 Normal Human Tissues with a
cDNA Microarray,” DNA Research, Vol. 9, No. 2, 2002,
pp. 35-45. doi:10.1093/dnares/9.2.35
[45] R. Shyamsundar, Y. H. Kim, J. P. Higgins, K. Montgomery, M. Jorden, et al., “A DNA Microarray Survey of
Gene Expression in Normal Human Tissues,” Genome
Biology, Vol. 6, No. 3, 2005, p. R22.
doi:10.1186/gb-2005-6-3-r22
[46] G. Son, S. Bilke, S. Davis, B. T. Greer, J. S. Wei, et al.,
“Database of mRNA Gene Expression Profiles of Multiple Human Organs,” Genome Research, Vol. 15, No. 3,
2005, pp. 443-450. doi:10.1101/gr.3124505
[47] J. Briggs, M. Paoloni, Q. R. Chen, X. Wen, J. Khan and C.
Khanna, “A Compendium of Canine Normal Tissue Gene
Expression,” PLoS One, Vol. 6, No. 5, 2011, pp. 101-107.
doi:10.1371/journal.pone.0017107
[48] E. A. Ostrander, F. Galibert and D. F. Patterson, “Canine
Genetics Comes of Age,” Trends in Genetics, Vol. 16, No.
3, 2000, pp. 117-123.
doi:10.1016/S0168-9525(99)01958-7
[49] D. Patterson, “Companion Animal Medicine in the Age
of Medical Genetics,” Journal of Veterinary Internal Medicine, Vol. 14, No. 1, 2000, pp. 1-9.
doi:10.1111/j.1939-1676.2000.tb01492.x
[50] M. Breen, et al., “Chromosome-Specific Single-Locus
FISH Probes Allow Anchorage of an 1800 Marker Integrated Radiation-Hybrid/Linkage Map of the Domestic
Dog Genome to All Chromosomes,” Genome Research,
JCT
Dogs: Active Role Model for Cancer Studies—A Review
Vol. 11, No. 10, 2001, pp. 1784-1795.
doi:10.1101/gr.189401
[51] M. Breen, J. Bullerdiek and C. F. Langford, “The DAPI
Banded Karyotype of the Domestic Dog (Canis Familiaris)
Generated Using Chromosome-Specific Paint Probes,”
Chromosome Research, Vol. 7, No. 5, 1999, pp. 401-406.
doi:10.1023/A:1009224232134
[52] M. Breen, et al., “An Integrated 4249 Marker FISH/RH
Map of the Canine Genome,” BMC Genomics, Vol. 5,
2004, p. 65. doi:10.1186/1471-2164-5-65
[53] C. Hitte, et al., “Facilitating Genome Navigation: Survey
Sequencing and Dense Radiation-Hybrid Gene Mapping,”
Nature Reviews Genetics, Vol. 6, No. 8, 2005, pp. 643648. doi:10.1038/nrg1658
[54] R. Li, et al., “Construction and Characterization of an
Eightfold Redundant Dog Genomic Bacterial Artificial
Chromosome Library,” Genomics, Vol. 58, No. 1, 1999,
pp. 9-17. doi:10.1006/geno.1999.5772
[55] E. F. Kirkness, et al., “The Dog Genome: Survey Sequencing and Comparative Analysis,” Science, Vol. 301, No.
5641, 2003, pp. 1898-1903. doi:10.1126/science.1086432
[56] N. Sutter and E. Ostrander, “Dog Star Rising: The Canine
Genetic System,” Nature Reviews Genetics, Vol. 5, No.
12, 2004, pp. 900-910. doi:10.1038/nrg1492
995
2037-2048. doi:10.1126/science.8091226
[62] X. Lu, Z. C. Wang, J. D. Iglehart, X. Zhang and A. L.
Richardson, “Predicting Features of Breast Cancer with
Gene Expression Patterns,” Breast Cancer Research and
Treatment, Vol. 108, No. 2, 2008, pp. 191-201.
doi:10.1007/s10549-007-9596-6
[63] B. Weigelt, Z. Hu, X. He, C. Livasy, L. A. Carey, M. G.
Ewend, A. M. Glas, C. M. Perou and L. J. Van’t Veer,
“Molecular Portraits and 70-Gene Prognosis Signature
Are Preserved throughout the Metastatic Process of Breast Cancer,” Cancer Research, Vol. 65, No. 20, 2005, pp.
9155-9158. doi:10.1158/0008-5472.CAN-05-2553
[64] L. J. Van‘t Veer, H. Dai, M. J. Van de Vijver, Y. D. He,
A. A. Hart, M. Mao, H. L. Peterse, K. Van der Kooy, M.
J. Marton, A. T. Witteveen, et al., “Gene Expression Profiling Predicts Clinical Outcome of Breast Cancer,” Nature, Vol. 415, No. 6871, 2002, pp. 530-536.
doi:10.1038/415530a
[65] P. Uva, L. Aurisicchio, J. Watters, A. Loboda, A. Kulkarni, J. Castle, F. Palombo, V. Viti, G. Mesiti, V. Zappulli, et al., “Comparative Expression Pathway Analysis
of Human and Canine Mammary Tumors,” BMC Genomics, Vol. 10, No. 135, 2009, p. 135.
doi:10.1186/1471-2164-10-135
[57] F. Galibert, C. Andre and C. Hitte, “Dog as a Mammalian
Genetic Model [in French],” Medicine Science (Paris),
Vol. 20, No. 8-9, 2004, pp.761-766.
[66] K. Strauch, et al., “How to Model a Complex Trait. General Considerations and Suggestions,” Human Heredity,
Vol. 55, No. 4, 2003, pp. 202-210.
doi:10.1159/000073204
[58] R. Klopfleisch, D. Lenze, M. Hummel and A. D. Gruber,
“Metastatic Canine Mammary Carcinomas can be Identified by a Gene Expression Profile That Partly Overlaps
with Human Breast Cancer Profiles,” BMC Caner, Vol.
10, 2010, p. 618. doi:10.1186/1471-2407-10-618
[67] E. K. Karlsson and K. Lindblad-Toh, “Leader of the Pack:
Gene Mapping in Dogs and Other Model Organisms,”
Nature Reviews Genetics, Vol. 9, No. 9, 2008, pp. 713725. doi:10.1038/nrg2382
[59] A. Nieto, M. D. Perez-Alenza, N. Del Castillo, E. Tabanera, M. Castano and L. Pena, “BRCA1 Expression in
Canine Mammary Dysplasias and Tumours: Relationship
with Prognostic Variables,” Journal of Comparative Pathology, Vol. 128, No. 4, 2003, pp. 260-268.
doi:10.1053/jcpa.2002.0631
[60] S. K. Muthuswamy, D. Li, S. Lelievre, M. J. Bissell and J.
S. Brugge, “ErbB2, But Not ErbB1, Reinitiates Proliferation and Induces Luminal Repopulation in Epithelial Acini,” Nature Cell Biology, Vol. 3, No. 9, 2001, pp. 785792. doi:10.1038/ncb0901-785
[61] E. S. Lander and N. J. Schork, “Genetic Dissection of
Complex Traits,” Science, Vol. 265, No. 5181, 1994, pp.
Copyright © 2013 SciRes.
[68] T. A. Manolio, et al., “Finding the Missing Heritability of
Complex Diseases,” Nature, Vol. 461, No. 7265, 2009,
pp. 747-753. doi:10.1038/nature08494
[69] M. Paoloni and C. Khanna, “Translation of New Cancer
Treatments from Pet Dogs to Humans,” Nature Reviews
Genetics, Vol. 8, No. 2, 2008, pp. 147-156.
doi:10.1038/nrc2273
[70] H. G. Parker, A. L. Shearin and E. A. Ostrander, “Man’s
Best Friend Becomes Biology’s Best in Show: Genome
Analyses in the Domestic Dog,” Annual Reviews of Genetics, Vol. 44, 2010, pp. 309-336.
doi:10.1146/annurev-genet-102808-115200
JCT